Mutant mice with visual defects serve as a resource for the study of the function and development of the mammalian retina. Currently, over 25 different mouse mutants have been shown to have visual defects. Using monoclonal antibodies that label specific antigens, morphological and structural abnormalities may be uncovered that correlate with the functional defects in these visual mutants. These mutants may also serve as animal models of various human diseases. Two major problems have been encountered in generating monoclonal antibodies: first, when immunizing with complex tissue (i.e., whole retina) a stereotyped immune response, largely to intermediate filaments, is found; second, even if antibodies to other than intermediate filaments could be found, there is no way to direct the immune response to differences between the mutant and the normal tissue. Recently, a new technique (immuno-suppression followed by in vitro immunization) has become available which increases the diversity of the immune response by minimizing immunodominance and suppression, and may also allow the generation of monoclonal antibodies to molecular differences between a mutant tissue and its wild type control. This approach may allow the defective gene product in mutant mice to be identified both morphologically and biochemically. Preliminary results have supported this idea; twenty-five new antibodies (four different classes) were produced from two fusions. Using this protocol and pitting rd/rd retina against normal retina resulted in an antibody against peripheral photoreceptor outersegments and not central photoreceptors.